In recent years, the issue of cleaning validation in pharmaceutical manufacturing processes has grown significantly. The purpose of cleaning validation is to accurately verify that potentially harmful compounds have been removed (below acceptable limits) from surfaces in process equipment prior to its use for another purpose. In the pharmaceutical industry, the need for adequate verifiable cleaning, and thus cleaning validation, occurs in a number of instances, as for example when equipment is used for processing two or more different active pharmaceutical ingredients sequentially or wherever cross-contamination between the products can have deleterious consequences. Additionally, it may be desirable to insure that the surfaces of process equipment do not contain residue from cleaning agents used in the cleaning process. Adequate cleaning of pharmaceutical process equipment is essential for the production of high quality pharmaceuticals, the elimination of contaminated drugs, and the avoidance of disruption of the manufacturing processes (with the possible consequence of losing the availability of essential drugs).
Increased interest in cleaning validation during the past several years has been driven by a number of factors. One factor for this increased interest is the attentiveness to cleaning validation by regulatory agencies. Highly publicized instances of pharmaceutical contamination, such as the 2004 contamination of approximately one-half of the United States influenza vaccine, are likely to further enhance industry awareness and regulatory attentiveness to the problem. Another factor for the increased interest is the trend toward the use of pharmaceutical manufacturing equipment and facilities for the manufacture of multiple products to increase manufacturing efficiency. A rapid, inexpensive verifiable method of validating adequate cleaning of pharmaceutical process equipment and process line significantly promotes the economic viability of using the equipment for multiple products. Among other advantages, utilizing pharmaceutical manufacturing equipment and facilities for multiple products facilitates cost-efficient development of pharmaceuticals for smaller demographics.
Prior art approaches to cleaning validation have focused upon collecting samples of residues on the surfaces to be validated, followed by quantitative analysis of the collected samples. Traditionally, this has been done either by analyzing samples collected by swabbing a portion of the surface or by analyzing a rinse matrix collected after the surface has been cleaned. These prior art methods have substantial shortcomings. Swabbing techniques require manually swabbing the entire surface of interest to assure complete coverage, and necessitate time-consuming analysis of the swabs. Additionally, manual swabbing procedures are prone to incomplete analyte recovery from the surface or the swap. Total analysis time for the swabbing technique is extensive, resulting in lengthy downtimes for the pharmaceutical process equipment. Although rinse matrix testing does include sampling from the entire surface, this technique includes a more difficult method validation, dilution and analyte solubility and detachment issues. Like the swabbing technique, rinse testing disadvantageously requires estimation of the quantity of analyte remaining on the surface.
It also is desirable to evaluate pharmaceutical products for certain desired characteristics. For example, in the manufacture of pharmaceutical tablets, it is desirable to control such characteristics as the hardness and moisture content of drugs in tablet form. Appropriate hardness of the tablet insures that the tablet will meet any required friability standards by retaining its structural integrity and not crumbling or powderizing prior to usage. Control of the moisture content of pharmaceutical tablets also is important, particularly for biotechnology products. Moisture content below an optimal level may allow the ingredients of the tablet to denature. Moisture content above an optimal level may allow the ingredients of the tablet to react. While tablets and other object can be tested for characteristics such as hardness and moisture content, prior art testing for these characteristics typically is conducted only on a sample basis (as for example on a sample size equal to the square root of n+1 for n tablets), involves substantial time and effort, and results in destruction of the tested samples.